Herpes virus is the etiological agent in a variety of infections, including diseases of the skin, mucous membranes, eye, or nervous system. A characteristic feature of herpes infection is its reactivation from latent form, leading to recurrence of symptoms, e.g., sores, long after initial infection.
There is no effective or clinically acceptable treatment of herpes to prevent reactivation of latent virus. Acyclovir (2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one) is prescribed in megadoses on a prophylactic basis for individuals with frequent recurrences. By definition, since acyclovir is a prodrug for a triphosphate derivative which inhibits the viral polymerase, this drug can only act to kill the virus after reactivation has already occurred. Thymidine kinase ("TK") inhibitors are useful for interfering with the reactivation process. TK inhibitors are also useful for depleting the number of cells with reactivatable latent virus.
Previously known TK inhibitors have one or more of the following disadvantages: biochemical actions other than TK inhibition with resulting undesired side effects; metabolic breakdown products that are genotoxic; insolubility, which complicates evaluation in animals; or low potency.
The first principal finding of the present invention is that the enantiomer L-758,340 is a potent inhibitor of herpes thymidine kinase.
Applicants have discovered that the enantiomer ##STR2## is substantially more active as an inhibitor of herpes thymidine kinase than its enantiomer ##STR3## The racemate of L-758,340 and L-758,341 is known, see e.g., U.S. Pat. No. 4,782,062.
A second principal finding of the present inventions is that certain prodrag types of L-758,340 have advantages in pharmacodynamics and physical properties, and are useful in the treatment or prevention of reactivation of herpes virus infections.
Applicants provide a novel synthetic route for the enantio selective synthesis of L-758,340. The key step in the synthesis is a lipase based hydrolysis of a prochiral diacetate. This hydrolysis gives excellent chemical yields and stereo selectivity but also can be easily scaled up to produce large quantities of optically active material.